Fstl1 suppresses breast cancer lung metastasis by inhibiting M2-like tumor-associated macrophages recruitment towards the lung

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Abstract
Immune cell infiltration in the tumor microenvironment is associated with cancer prognosis. Tumor-associated macrophages (TAMs) play an essential role in tumor initiation, progression, and metastasis. Follistatin-like protein 1 (Fstl1), a glycoprotein widely expressed in human and mouse tissues, is a tumor suppressor in various cancers and a regulator in macrophage polarization. However, how Fstl1 affects the crosstalk between breast cancer cells and macrophages remains unclear. Analyzing the public data, we found that Fstl1 expression significantly decreases in breast cancer tissues compared with normal breast tissues, and high expression of Fstl1 in patients means prolonged survival. Using flow cytometry, we found that total macrophages and M2-like macrophages increased in the metastatic lung tissues during breast cancer lung metastasis of Fstl1+/- mice. Cellular experiments in vitro showed that Fstl1 inhibited macrophage migration towards 4T1 cells via decreasing colony stimulating factor 1 (CSF-1), transforming growth factor-β1 (TGFB1) and vascular endothelial growth factor-α (VEGF-α) expression of 4T1 cells. We demonstrated that Fstl1 inhibited M2-like tumor-associated macrophages recruitment towards the lung and suppressed TGFB1/Smad2/3 pathway and relevant cytokines expression of 4T1 cells. Thereby we find a potential therapeutic strategy contributing to breast cancer.

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